1. Field of the Invention
This invention relates to a so-called partial synthesis process for preparing (+)-vincamine and related indolic alkaloids, which may be represented by the general formula (I): ##STR1## wherein: (a) when X=Y=H, R'=--OH, R=--COOCH.sub.3, formula (I) represents vincamine,
(b) when X=Y=H, R'=--COOCH.sub.3, R=--OH, formula (I) represents 16-epivincamine, PA0 (c) when X+Y=a double bond, R'=--OH, R=--COOCH.sub.3, formula (I) represents .DELTA..sup.14 -vincamine, PA0 (d) when X+Y=a double bond, R'=--COOCH.sub.3, R=--OH, formula (I) represents .DELTA..sup.14 -16-epivincamine. PA0 (a) extractive method; PA0 (b) total synthesis; and PA0 (c) partial synthesis. PA0 (f) when X+Y=a double bond, formula (II) represents tabersonine PA0 a compound of general formula (II): ##STR3## wherein: (e) when X=Y=H, formula (II) represents vincadifformine, and PA0 the reaction medium comprising a low molecular weight alcohol, a trialkyl phosphite as a reducing agent and the photosensitizer is prepared, PA0 the substrate is added to the reaction medium, the trialkyl phosphite being present in a stoichiometrical excess with respect to the substrate, PA0 the thus formed reaction mixture is subjected to gaseous oxygen blowing under substantially ambient temperature and pressure conditions and at the same time the mixture is subjected to an irradiation from a light source in order to activate oxygen in situ, for a time not exceeding 150 minutes, thus obtaining oxidation of the substrate and a resulting reduction, PA0 the treated reaction mixture is acidified, alkalized and extracted, PA0 and finally the extraction residue is subjected to fractional crystallization and/or column chromatography in order to separate distinct products in the pure state, having the general formula (I).
2. Description of Relevant Art
Vincamine is a member of a class of indolic alkaloids having interesting pharmacological properties, in particular of the hypotensive, sedative and cerebral metabolism activating kinds.
These characteristics render vincamine to be the active principal ingredient of effective drugs in the treatment of diseases of the circulatory system and of the central nervous system.
Methods for preparing vincamine and other indolic alkaloids on an industrial scale can be grouped into three distinct types of methods:
Processes of direct extraction from vegetal species have limited applications due to the fact that, among plants, which are known as possible sources of vincamine, such a substance is contained therein in a very low amount (0.1-0.2%). This fact makes the extraction processes and more particularly the purification processes substantially complex and difficult, and is the cause of the high disproportion existing between the amount of starting vegetal product, solvents and reagents required, and the amount of substance obtained with an acceptable purity level.
The processes of total synthesis, or preparation from simple chemical compounds which are readily commercially available, present the advantage of requiring no vegetal products. However, due to the complexity of the chemical structure of vincamine, all the processes of this kind comprise a large number of steps, which together with other intrinsic problems (i.e., stereoselectivity of the reactions, separations of diastereoisomers and finally the obtaining of (+)-vincamine from racemic vincamine) cause significant decreases in the yield of final product. In processes of partial synthesis of compounds represented by formula (I), one particular process provides for use of structurally complex substances as starting materials, such as vincadifformine and tabersonine which are compounds included in the series of compounds represented by general formula (II): ##STR2## wherein: (e) when X=Y=H, formula (II) represents vincadifformine, and
Compounds (II) are obtainable with a good yield from vegetal species which are widespread in nature. Vincadifformine can also be suitably prepared by catalytic hydrogenation of tabersonine [N. N. Janot, J. Le Men, Compt. Rend. Acad. Sci. 248,3005 (1959) et N. Plat, J. Le Men et N. N. Janot, Tetr. lett. 271 (1962)]. The substances (II) are then transformed into compounds (I) through a limited series of chemical steps.
Various processes of partial synthesis of vincamine or related alkaloids have been proposed, more particularly aiming at simplifying the operative steps and reducing duration thereof. An advance in this respect has been obtained with the reaction of direct oxidation of vincadifformine and/or tabersonine, in direct combination with specific compounds. French Pat. Nos. 75-24708 and 76-21432 can be cited in this connection. French Pat. No. 75-24708 describes a process for preparing vincamine and related alkaloids this process being based on the treatment of vincadifformine and/or tabersonine with oxygen over extended periods (5-10 days) in the presence of salts of copper, iron or cobalt, in an acid hydroalcoholic reaction medium. The main product and others are isolated by column chromatography of the crude reaction product. French Pat. No. 76-21432 describes a process according to which vincadifformine or tabersonine is first treated with sodium hydride in anhydrous tetrahydrofuran and hexamethylene phosphortriamide, in mixture with anhydrous dimethylformamide and toluene, in the presence of trimethyl phosphite. Thereafter, the solution is maintained under an oxygen atmosphere, then acidified and conventionally treated. The crude reaction product is finally subjected to column chromatography and thus vincamine is obtained with a yield of 28%.
The foregoing processes, while they may have adopted more acceptable techniques with respect to prior processes maintain, however, as in French Pat. No. 75-24708 operation durations which are still too long or, as in the case of French Pat. No. 76-21432, operating conditions which require difficult manipulation of reactants and restrictive and critical conditions of working temperature.
In other terms, vincadifformine and tabersonine, which are inert to the direct action of elementary oxygen, become reactive only in the presence of metal compounds (French Pat. No. 75-24708) or strong bases (French Pat. No. 76-21432) (which in an anhydrous environment transform vincadifformine and tabersonine into respective bidentated anions), because under these reactions a reaction between the thus activated substrates and elementary oxygen provides desired products in varying yields.